The Investigation of Hypocalcaemia and Rickets J Singh, N Moghal,Shspearce, T Cheetham

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REVIEW Arch Dis Child: first published as 10.1136/adc.88.5.403 on 1 May 2003. Downloaded from The investigation of hypocalcaemia and rickets J Singh, N Moghal,SHSPearce, T Cheetham ......

Arch Dis Child 2003;88:403–407 Our understanding of disorders that present with fluid is detected by this receptor, and leads to hypocalcaemia has advanced rapidly in the past enhanced PTH secretion by the parathyroid chief cell. PTH is the principle calcitropic peptide in decade. The molecular basis of many of these disorders humans; its effects on tissues like kidney, bone, and conditions associated with phosphate wasting has and intestine are primarily mediated through the now been established. While many children will need parathyroid hormone receptor (PTH/PTHrP receptor).6 These effects can be summarised as specialist involvement, they often will present to general follows: paediatricians, and appropriate investigations prior to • Increased reabsorption of calcium by the distal intervention will enable early diagnosis. Not all children renal tubule. with hypocalcaemia and low or low normal parathyroid • Mobilisation of calcium reserves from bone. hormone levels have isolated hypoparathyroidism, and • Enhanced 1 alpha hydroxylation of vitamin D to 1,25 dihydroxyvitamin D by the kidney. This clinicians need to be aware of the potential for in turn increases intestinal calcium absorption misdiagnosis. Outpatient departments and paediatric and serum calcium levels. wards should have a readily accessible and • Increased renal phosphate excretion. comprehensive list of bloods that need to be taken when a child presents with hypocalcaemia or rickets. HYPOCALCAEMIA AND RICKETS ...... Deficiency or impaired function of one of the three main determinants of circulating calcium concentrations outlined above (vitamin D, PTH, stablishing the diagnosis in patients with and the calcium sensing receptor) can lead to hypocalcaemia and rickets can be difficult. hypocalcaemia. The main causes of hypocalcae- EThere is a wide and expanding range of mia include: underlying disorders, some of which are ex- • Vitamin D deficiency

tremely rare. Recognition and understanding of http://adc.bmj.com/ diseases such as hypocalcaemic hypercalciuria; • Impaired vitamin D metabolism hypoparathyroidism, deafness, and renal dyspla- • Calcium deficiency sia (HDR syndrome); autoimmune polyglandular • Reduced PTH production endocrinopathy with candidiasis and ectodermal dystrophy (APECED); and the various forms of • Impaired PTH action due to end organ resist- hypophosphataemic rickets has advanced consid- ance erably over the past decade and has made the • An abnormal calcium sensing receptor assessment of this patient group more • Impaired renal function. on October 1, 2021 by guest. Protected copyright. complex.1–4 While this area of practice may primarily be of interest to the subspecialist, the The above can influence calcium concentrations general paediatrician will be confronted with in the newborn period, but babies are also subject children with hypocalcaemia and rickets, and to insults that can affect calcium homoeostasis, knowledge of what constitutes an appropriate such as prematurity, asphyxia, and maternal investigation and management plan is important. hyperglycaemia. A definitive diagnosis will frequently not be made Rickets is a disorder of growing children in at the first encounter with the patient, but a com- which the newly formed bone matrix is not min- prehensive range of investigations before inter- eralised appropriately. It reflects a deficiency of vention will help to ensure that treatment is the bone constituents, calcium, and/or phosphate. appropriate. Some children with hypocalcaemia will be found See end of article for to have rickets, but not all children with rickets authors’ affiliations ...... will be hypocalcaemic. Rickets can be classified according to the underlying pathology into three CALCIUM HOMOEOSTASIS Correspondence to: main groups: vitamin D deficiency, calcium Maintenance of serum calcium levels in the Dr T D Cheetham, deficiency, or phosphate deficiency. Department of Paediatrics, physiological range is a complex process that Royal Victoria Infirmary, reflects the function of, and interaction between, Queen Victoria Road, Newcastle upon Tyne vitamin D, parathyroid hormone (PTH), and the ...... NE1 4LP, UK; calcium sensing receptor. Abbreviations: [email protected] The calcium sensing receptor was characterised APECED, autoimmune polyglandular endocrinopathy with candidiasis and ectodermal in 19935 and is found on the cell surface of tissues Accepted dystrophy; HDR, hypoparathyroidism, deafness, and renal 5 October 2002 such as the parathyroid gland, kidney, and bone. dysplasia; PTH, parathyroid hormone; PTHrP, parathyroid ...... A lowering of ionised calcium in extracellular hormone receptor

www.archdischild.com 404 Singh, Moghal, Pearce, et al

Vitamin D deficiency or resistance This may be caused by: Table 1 First and second line investigations in patients with hypocalcaemia and rickets Arch Dis Child: first published as 10.1136/adc.88.5.403 on 1 May 2003. Downloaded from • Dietary deficiency. • Lack of sunlight exposure. First line Second line • Malabsorption. Blood Calcium/phosphate Karyotype • Liver disease and drug associated dysfunction (e.g. pheny- Alkaline phosphatase Autoantibody screen toin), resulting in failure to 25 hydroxylate vitamin D. Electrolytes and creatinine Parental/sibling biochemistry • Renal pathology with significant tubular damage. The asso- Bicarbonate Maternal vitamin D status PTH Thyroid function ciated 1 alpha hydroxylase deficiency leads to a failure to 1 Magnesium hydroxylate vitamin D appropriately. Vitamin D • An inherited deficiency of 1 alpha hydroxylase due to “Save serum” defects in the 1 alpha hydroxylase gene (vitamin D depend- 7 Urine ent rickets type I). Calcium Low molecular weight proteins • End organ resistance to vitamin D (vitamin D dependent Phosphate rickets type II).8 This disorder is usually due to mutations in pH Protein the vitamin D receptor and can be associated with alopecia. Glucose

Calcium deficiency Other investigations Dietary calcium deficiency without concomitant vitamin D Hand/wrist radiograph Renal ultrasound deficiency is described.910 EDTA sample for genetic studies Skull radiograph Phosphate deficiency This may be caused by: • Renal tubular loss because of specific genetic forms of renal phosphate wasting, such as hypophosphataemic rickets (X • Alkaline phosphatase levels. An appropriate, age related linked11–13 and dominant14 15 forms exist), as well as general- reference range should be used; an individual’s pubertal ised renal tubulopathies, such as Fanconi’s syndrome. status needs to be considered. Occasionally phosphate wasting can be associated with • PTH. benign or malignant tumours.16 17 • Plasma bicarbonate, looking for evidence of acidosis in • Inadequate phosphate intake, which is the main cause of association with Fanconi’s syndrome or renal tubular osteopenia of prematurity. acidosis. • Magnesium levels should always be checked in hypocalcae- PRESENTATION AND CLINICAL FEATURES mic patients. Severe hypomagnesaemia (<0.45 mmol/l) Hypocalcaemia may be an incidental finding, or it can result in causes hypocalcaemia by impairing PTH secretion as well as symptoms such as paraesthesia or cramps. Awareness of PTH action. hypocalcaemia as a cause of seizures is important because http://adc.bmj.com/ • Vitamin D (25-hydroxyvitamin D). children are still treated with anticonvulsants without serum calcium concentrations being checked. Children with congeni- • Save serum. This may be useful at a later date to measure tal heart defects and those with primary adrenal failure may 1,25 vitamin D if the picture suggests resistance to vitamin have their calcium concentrations measured routinely because D with high 25-hydroxy vitamin D levels. of the known association with hypoparathyroidism. Children The above investigations can usually be undertaken on 4–5 ml with rickets may present with limb deformity (both genu whole blood. varum and valgum), and in the case of the inherited forms of PTH undergoes cleavage to a variety of smaller peptides. rickets this is frequently noticed when the child starts to Only the N-terminal fragment has biological activity at the on October 1, 2021 by guest. Protected copyright. weight bear. Some children with vitamin D deficiency can PTH/PTHrP receptor, and the low circulating concentrations present with hypocalcemia without the typical skeletal combined with a short half life of 2–5 minutes mean that it phenotype.18 can be difficult to measure. The standard approach to determining circulating PTH concentrations uses a two site immunoassay (for example, the Nichols Advantage chemilu- AN INVESTIGATIVE APPROACH TO THE CHILD minescence immunoassay) which measures the intact pep- WITH HYPOCALCAEMIA AND RICKETS tide. Potassium/EDTA plasma or a serum (plain clotted) sam- A detailed history documenting diet, lifestyle, family, and drug ple should be collected and transported to the laboratory history, as well as development and hearing is important. The within one hour, or stored on ice if it is likely to be longer examination should include an assessment of skin, nails, before the sample is separated and frozen or analysed (about teeth, and the skeleton, as well as the cardiovascular system. A 1 ml whole blood is usually adequate). Blood can be processed comprehensive range of investigations should be performed at in this way out of normal working hours, and many biochem- baseline, analogous to the approach to hypoglycaemia in istry departments now provide a rapid turnaround. childhood (table 1). They have been divided here into blood, urine, and other potentially useful tests. Investigations on urine Investigations on blood • Calcium, phosphate, and creatinine in a spot urine sample. When this is being used to calculate renal tubular Calcium, phosphate, and creatinine in plasma. Ionised cal- • phosphate handling (see below), this needs to be taken cium should ideally be measured because this is the within two hours of the serum sample. biologically active component and is more accurate than “corrected” calcium levels derived from total calcium • Urinalysis for pH, protein, and glucose. concentrations. Calcium concentrations vary according to The main objective of assessing urine calcium excretion is to age, and an appropriate reference range needs to be used. establish whether this is inappropriately high in the presence

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Table 2 Principle causes of hypocalcaemia in childhood Arch Dis Child: first published as 10.1136/adc.88.5.403 on 1 May 2003. Downloaded from

Parathyroid hormone deficiency (low PTH levels) I. Parathyroid aplasia/hypoplasia or abnormal PTH production As part of 22q11 deletions 10p13 deletion CHARGE syndrome X linked hypoparathyroidism (1 family in the world to date) Autosomal dominant hypoparathyroidism Autosomal recessive hypoparathyroidism Syndrome of hypoparathyroidism, deafness, renal dysplasia (HDR) II. Type 1 autoimmune polyendocrinopathy III. Infiltrative lesions such as Wilson’s disease, thalassaemia III. Mitochondrial DNA mutations e.g. Kearns Sayre syndrome IV. Magnesium deficiency V. Neck surgery

Altered “set point” (normal or low normal parathyroid hormone levels) VI. Calcium sensing receptor activating mutation

Hypocalcaemia associated with increased PTH production (raised PTH levels) VII. Gsα and other signalling defects e.g. pseudohypoparathyroidism VIII. Vitamin D deficiency Figure 1 Calculate % TRP and then use this and the serum Nutritional phosphate to calculate TmP/GFR from the nomogram: % TRP = 1 − Malabsorption × × (UP Pcrea)/(Pp Ucrea). The inner axes are mmol/l and the outer axes IX. Calcium deficiency mg/100 ml. X. Impaired vitamin D metabolism Enzyme deficiency—defects of the 1 alpha hydroxylase gene (vitamin D dependent rickets type I) of a low plasma calcium. Reference values for urine End organ resistance to vitamin D (vitamin D dependent rickets type II) calcium/creatinine ratio in young children are not well defined XI. Renal failure and will vary according to factors such as diet. The upper limit XII. Magnesium deficiency (low and high PTH levels have been of normal (∼97th centile) for fasting urine calcium excretion reported) in healthy children greater than 2 years of age in the United XII. Osteopetrosis Kingdom is 0.69 mmol/mmol,19 but values may be greater than this in infancy. In the presence of hypocalcaemia a urine calcium/creatinine ratio greater than 0.3 mmol/mmol on spot samples suggests inappropriate excretion.20 A timed 24 hour urinary calcium excretion (collected in containers with Other investigations http://adc.bmj.com/ hydrochloric acid to prevent precipitation of calcium salts) can • A hand/wrist and/or knee radiograph if rickets is suspected. be obtained in the older child. Hypercalciuria is suggested by A skull film may occasionally provide further information values greater than 0.1 mmol/kg/day.21 Timed urine collection but is not necessary routinely. can be difficult in young children, and a random spot urine • Checking the plasma and urine biochemistry of both calcium creatinine ratio repeated on 2–3 occasions at the same parents and possibly siblings is crucial when inherited dis- time of day is frequently the most appropriate way of assess- eases such as hypocalcaemic hypercalciuria and hypophos- ing urine calcium excretion. The calcium:creatinine ratio on

phataemic rickets are suspected. It is also important to on October 1, 2021 by guest. Protected copyright. the second voided urine sample of the day after an overnight measure maternal calcium and vitamin D levels in the case 21 fast is most closely related to 24 hour urine calcium levels. of hypocalcaemia in infancy because of the link with Renal phosphate handling may be abnormal despite a maternal vitamin D deficiency and hyperparathyroidism. serum phosphate within the quoted laboratory normal range, Maternal hyperparathyroidism is associated with adverse and should be assessed in more detail by determining the pregnancy outcome and causes transient hypocalcemia in tubular maximum reabsorption threshold of phosphate per the newborn because the fetal parathyroids are suppressed glomerular filtration rate (TmP/GFR). The TmP/GFR can be following exposure to high calcium levels in utero. calculated using the nomogram (fig 1) or computer equation • An autoantibody screen including adrenal, parathyroid, and based on the work of Walton and Bijvoet and published in smooth muscle and LKM antibodies is useful in cases of 1975,22 or the following formula based on the work of Brodehl isolated hypoparathyroidism and where APECED is sus- and colleagues23: pected (see later). • Renal ultrasound scan looking for evidence of nephrocalcinosis or renal dysplasia. • Karyotype looking for 22q11 and 10p13 deletions.

Pp,Up,Pcrea, and Ucrea refer to plasma and urine concentrations THE INTERPRETATION OF BLOOD AND URINE of phosphate and creatinine. BIOCHEMISTRY TmP/GFR can be calculated in both fasting and non-fasting The biochemical picture can be categorised according to the children and should be compared with age appropriate refer- presence of undetectable, normal or high levels of PTH (table ence ranges. British reference data calculated using the 2). In our experience the initial diagnosis in patients present- Walton and Bijvoet formula provide a reference range for 2–15 ing with hypocalcaemia or rickets may be incorrect in as many year olds of 1.15–2.44 mmol/l.19 as 80% of cases (unpublished data); an approach that is linked

www.archdischild.com 406 Singh, Moghal, Pearce, et al to PTH concentrations can help to explain and understand the Learning points underlying pathophysiology and should help to improve diag- nostic accuracy. Arch Dis Child: first published as 10.1136/adc.88.5.403 on 1 May 2003. Downloaded from • Paediatric units should have a protocol for the investigation of patients with hypocalcaemia and rickets Undetectable or low PTH levels in the hypocalcaemic • The measurement of PTH should be undertaken prior to child intervention Undetectable or very low PTH values in the symptomatic child • Vitamin D deficiency may present with hypocalcaemia, suggest hypoparathyroidism (table 2). Aplasia or hypoplasia of without phenotypic changes of rickets the parathyroids is most commonly due to the DiGeorge/ • Vitamin D deficiency needs to be excluded in patients with velocardiofacial syndrome associated with deletion of chro- suspected pseudohypoparathyroidism mosome 22q11.2. A similar phenotype including hypoparathy- • A diagnosis of “isolated” hypoparathyroidism should only roidism has also been associated with deletions of be made when other disorders associated with hypocalcaemia, such as APECED and HDR syndrome, have been con- chromosome 10p and, recently, the HDR syndrome (hypopar- sidered athyroidism, deafness, and renal dysplasia) was found to be • The adult reference range for phosphate may be quoted, 2 due to defects in the GATA3 gene at 10p15. The HDR leading to abnormally low results being regarded as syndrome is an autosomal dominant disorder which can normal present with hypocalcaemia in early life, although the diagno- • The assessment of renal phosphate handling (TmP/GFR) is sis of hypoparathyroidism may be delayed by many years.24 the definitive way to exclude hypophosphataemic rickets Defects in the PTH gene are rare and can be associated with autosomal dominant and recessive isolated hypoparathyroidism.25 26 Mutations of the GCMB gene on the related/calcium deficiency rickets where the PTH is almost short arm of chromosome 6 can also cause recessively always raised and calcium concentrations normal or reduced. inherited hypoparathyroidism.27 Diseases such as polyglandular endocrinopathy type 1, also Increased PTH levels known as autoimmune polyglandular endocrinopathy with If the serum creatinine is normal, thereby excluding renal candidiasis and ectodermal dystrophy (APECED), can present insufficiency, then increased PTH levels point towards a diag- with hypoparathyroidism in the absence of the two other nosis of vitamin D related/calcium deficiency rickets or pseu- major manifestations, which are candidiasis and adrenal dohypoparathyroidism (see table 1). Vitamin D deficiency is failure.28 There should be a high index of suspicion for this still prevalent in the Western world,32 33 and it is important to disease in all cases of hypoparathyroidism presenting in chil- remember that this may present with hypocalcaemia before dren older than 4 years.29 Children with APECED may have the typical clinical phenotype develops.34 A detailed history other “minor” features such as malabsorption, gallstones, looking for evidence of dietary deficiency or gut dysfunction is hepatitis, dysplastic nails and teeth, and do not always have mandatory in all children with hypocalcaemia or rickets. circulating autoimmune markers. APECED has an autosomal Physical findings of fatigue, myalgia, and weakness may recessive pattern of inheritance and is caused by mutations of accompany bony deformities. Genu valgum (knock knees) the autoimmune regulator (AIRE) gene.3 Screening should be may occur as well as the more typical genu varum (bow considered in the siblings of affected individuals. Mito- legged) appearance. High risk groups include Asian families, chondrial disease is a rare cause of hypoparathyroidism but is where the maternal and child diet may be low in calcium and 30 35 not usually an isolated finding. vitamin D and where exposure to sunlight can be limited. http://adc.bmj.com/ Maternal vitamin D levels should always be checked in Detectable PTH values (low-normal or normal) neonates with vitamin D deficiency. The diagnosis of Fanconi Detectable PTH values (low-normal or normal) in an syndrome should be considered in any child with persistent asymptomatic individual raise the possibility of an abnormal- glycosuria, phosphaturia, and acidosis. Measurement of low β ity of the calcium sensing receptor which can be assessed in molecular weight urine proteins ( 2 microglobulin or retinol more detail by determining urinary calcium excretion. Urine binding protein) should confirm the diagnosis.36 calcium excretion is typically low in longstanding hypopara- Pseudohypoparathyroidism is a heterogeneous disorder thyroidism, and a relatively high urine calcium excretion that is frequently associated with abnormalities of the G pro- on October 1, 2021 by guest. Protected copyright. (urine Ca:Cr ratio >0.3 mmol/mmol) suggests hypocalcaemic tein component adjacent to the PTH and other G protein cou- hypercalciuria.1 Hypocalcaemic hypercalciuria is due to pled cell surface receptors. Patients may become hypocalcae- activating mutations of the calcium sensing receptor which mic despite a compensatory increase in PTH concentrations, downshift the set point for calcium responsive PTH release. and may have other endocrine problems, such as primary Serum calcium levels are relatively refractory to change in hypothyroidism and hypogonadism that are also manifesta- response to vitamin D analogues, but urine calcium greatly tions of an abnormal signalling mechanism.37 38 Not all increases with an associated risk of nephrocalcinosis. Magne- patients are overweight and many are of normal intelligence. sium levels are low in this disorder because the calcium sensing receptor also detects this cation (see table 1). Intervention ...... can also lead to the development of symptoms in previously Authors’ affiliations well patients; this may reflect PTH suppression with a result- J Singh, N Moghal, T Cheetham, Department of Paediatrics, Royal ant failure of acute “minute to minute” regulation of serum Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, UK SHSPearce, calcium. Hypocalcaemic hypercalciuria may be sporadic or Department of Endocrinology, Royal Victoria Infirmary have an autosomal dominant pattern of inheritance, and REFERENCES screening may identify an asymptomatic parent. Interestingly, 1 Pearce S, Williamson C, Kifor O, et al. A familial syndrome of mutations that fully activate the calcium sensing receptor hypocalcemia with hypercalciuria due to mutations in the calcium-sensing have recently been associated with the development of receptor. N Engl J Med 1996;335:1115–22. Bartter’s syndrome.31 The patients reported actually had 2 Van Esch H, Groenen P, Nesbit M, et al. 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Fetal and Neonatal Edition, May 2003 on October 1, 2021 by guest. Protected copyright. The following articles—being published in the May 2003 issue of the Fetal and Neonatal edition of the Archives of Disease in Childhood—may be of general interest to paediatricians. Original articles Long term outcome of neonatal meningitis. J P Stevens, M Eames, A Kent, S Halket, D Holt, D Harvey Congenital brachial palsy: incidence, causes, and outcome in the United Kingdom and Republic of Ireland. G Evans-Jones,SPJKay, A M Weindling, G Cranny, A Ward, A Bradshaw, C Hernon Health and school performance of teenagers born before 29 weeks gestation. A Johnson, U Bowler, P Yudkin, C Hockley, U Wariyar, F Gardner, L Mutch